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WO2009021747A2 - Traitement de la dystrophie musculaire de duchenne - Google Patents

Traitement de la dystrophie musculaire de duchenne Download PDF

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Publication number
WO2009021747A2
WO2009021747A2 PCT/EP2008/006717 EP2008006717W WO2009021747A2 WO 2009021747 A2 WO2009021747 A2 WO 2009021747A2 EP 2008006717 W EP2008006717 W EP 2008006717W WO 2009021747 A2 WO2009021747 A2 WO 2009021747A2
Authority
WO
WIPO (PCT)
Prior art keywords
compound
muscular dystrophy
formula
compounds
treatment
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2008/006717
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English (en)
Other versions
WO2009021747A3 (fr
Inventor
Graham Michael Wynne
Olivier De Moor
Cristina Lecci
Renate Van Well
Peter David Johnson
Richard Storer
Severine Poignant
Stephen Paul Wren
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Summit Therapeutics Ltd
Original Assignee
Summit Corp PLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Summit Corp PLC filed Critical Summit Corp PLC
Priority to AU2008286323A priority Critical patent/AU2008286323A1/en
Priority to EP08785564A priority patent/EP2176230A2/fr
Priority to JP2010520497A priority patent/JP2010535828A/ja
Priority to CA002685582A priority patent/CA2685582A1/fr
Priority to US12/599,967 priority patent/US20120149741A1/en
Publication of WO2009021747A2 publication Critical patent/WO2009021747A2/fr
Publication of WO2009021747A3 publication Critical patent/WO2009021747A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C07D249/18—Benzotriazoles
    • C07D249/20—Benzotriazoles with aryl radicals directly attached in position 2

Definitions

  • DMD Duchenne muscular dystrophy
  • DMD has been characterized as an X-linked recessive disorder that affects 1 in 3,500 males caused by mutations in the dystrophin gene.
  • the gene is the largest in the human genome, encompassing 2.6 million base pairs of DNA and containing 79 exons.
  • Approximately 60% of dystrophin mutations are large insertion or deletions that lead to frameshift errors downstream, whereas approximately 40% are point mutations or small frameshift rearrangements.
  • Becker muscular dystrophy is a much milder form of DMD caused by reduction in the amount, or alteration in the size, of the dystrophin protein.
  • the high incidence of DMD (1 in 10,000 sperm or eggs) means that genetic screening will never eliminate the disease, so an effective therapy is highly desirable.
  • mdx chromosome-linked muscular dystrophy
  • the mdx mouse is the most widely used model due to availability, short gestation time, time to mature and relatively low cost (Bulfield, G., Siller, W. G., Wight, P. A. & Moore, K. J. X chromosome-linked muscular dystrophy (mdx) in the mouse. Proc. Natl Acad. Sci. USA 81, 1189-1192 (1984)). Since the discovery of the DMD gene about 20 years ago, varying degrees of success in the treatment of DMD have been achieved in preclinical animal studies, some of which are being followed up in humans.
  • Gene- and cell-based therapies offer the fundamental advantage of obviating the need to separately correct secondary defects/ pathology (for example, contractures), especially if initiated early in the course of the disease.
  • secondary defects/ pathology for example, contractures
  • these approaches face a number of technical hurdles.
  • Immunological responses against viral vectors, myoblasts and newly synthesized dystrophin have been reported, in addition to toxicity, lack of stable expression and difficulty in delivery.
  • Pharmacological approaches for the treatment of muscular dystrophy differ from gene- and cell-based approaches in not being designed to deliver either the missing gene and/or protein.
  • the pharmacological strategies use drugs/molecules in an attempt to improve the phenotype by means such as decreasing inflammation, improving calcium homeostasis and increasing muscle progenitor proliferation or commitment.
  • These strategies offer the advantage that they are easy to deliver systemically and can circumvent many of the immunological and/or toxicity issues that are related to vectors and cell-based therapies.
  • investigations with corticosteroids and sodium cromoglycate, to reduce inflammation, dantrolene to maintain calcium homeostasis and clenbuterol to increase muscle strength have produced promising results none of these potential therapies has yet been shown to be effective in treating DMD.
  • Upregulation therapy is based on increasing the expression of alternative genes to replace a defective gene and is particularly beneficial when an immune response is mounted against a previously absent protein.
  • Upregulation of utrophin an autosomal paralogue of dystrophin has been proposed as a potential therapy for DMD (Perkins & Davies, Neuromuscul Disord, Sl : S78- S89 (2002), Khurana & Davies, Nat Rev Drug Discov 2:379-390 (2003)).
  • DAPC dystrophin-associated protein complex
  • a 1 , A 2 , A 3 , and A 4 represent CH and one of A 1 , A 2 , A 3 , and A 4 represents CR 1 ;
  • R 1 represents SO 2 R 2 or NHCOR 2 wherein R 2 represents C 1 -C 6 alkyl optionally substituted by one or more halogen, hydroxyl or alkoxy groups (Cj-C 6 alkoxy groupy);
  • R 9 represents aryl optionally substituted by one or more halogen groups; or a pharmaceutically acceptable salt thereof.
  • Figure 1 shows a luciferase reporter assay (murine H2K cells).
  • Figure 2 shows a dose dependent luciferase induction.
  • Figure 3 shows an example of TA muscle sections stained with antibody specific for mouse utrophin.
  • Figure 4 shows that mice exposed to CPD-A (V2 and V3) showed increased levels of utrophin expression compared to control.
  • a 1 , A 2 , A 3 , and A 4 are defined as above, in a reductive ring closure effected by reaction with thiourea-S,S-dioxide or a dithionite salt, for example an alkali metal salt, as described, for example, in EP 0 751 134.
  • the reaction may be carried out in an aqueous solution, in another embodiment an alcoholic aqueous solution, at a temperature of 60 to 8O 0 C. Cyclisation will not occur in the presence of certain functionality, for example in the presence of -NH 2 or -OH functionality. These groups will need to be protected before cyclisation. For example -NH 2 groups may be protected as amides, and OH groups may be protected as ethers. Suitable protecting strategies are disclosed, for example, in EP 0 751 Compounds of formula II may be prepared by a diazonium coupling reaction of a diazonium compound of formula III,
  • reaction may take place in methanol under slightly acidic conditions, over up to 24 hours.
  • a 1 , A 2 , A , and A are defined as above.
  • Methods of diazotisation are well known in the art, e.g. by reaction with NaNO 2 / AcOH in an aqueous solution at 0 to 1O 0 C.
  • a , A , A , and A 4 are as defined above and P represents a protecting group appropriate to the nitrating conditions.
  • Nitration could be effected by, for example, CHN(VcH 2 SO 4 in a solvent appropriate to the reaction conditions.
  • Suitable protecting groups and methods for their removal are, for example, those described in "Protective Groups in Organic Synthesis" by T. Greene and P.G.M. Wutts, John Wiley and Sons Inc., 1991.
  • Hydroxy groups may, for example, be protected by arylmethyl groups such as phenylmethyl, diphenylmethyl or triphenylmethyl; acyl groups such as acetyl, trichloroacetyl or trifluoroacetyl; or as tetrahydropyranyl derivatives.
  • Suitable amino protecting groups include aryimethyi groups such as benzyl, (R,S)- ⁇ -phenylethyl, diphenylmethyl or triphenylmethyl, and acyl groups such as acetyl, trichloroacetyl or trifluoroacetyl.
  • Conventional methods of deprotection may be used including hydrogenolysis, acid or base hydrolysis, or photolysis.
  • Arylmethyl groups may, for example, be removed by hydrogenolysis in the presence of a metal catalyst e.g. palladium on charcoal.
  • Tetrahydropyranyl groups may be cleaved by hydrolysis under acidic conditions.
  • Acyl groups may be removed by hydrolysis with a base such as sodium hydroxide or potassium carbonate, or a group such as trichloroacetyl may be removed by reduction with, for example, zinc and acetic acid.
  • the compounds of formula I, and salts thereof, may be isolated from their reaction mixtures using conventional techniques. Salts of the compounds of formula I may be formed by reacting the free acid, or a salt thereof, or the free base, or a salt or derivative thereof, with one or more equivalents of the appropriate base or acid.
  • the reaction may be carried out in a solvent or medium in which the salt is insoluble or in a solvent in which the salt is soluble, e.g. ethanol, tetrahydrofuran or diethyl ether, which may be removed in vacuo, or by freeze drying.
  • the reaction may also be a metathetical process or it may be carried out on an ion exchange resin.
  • salts of the compounds of formula I include alkali metal salts, e.g. sodium and potassium salts; alkaline earth metal salts, e.g. calcium and magnesium salts; salts of the Group III elements, e.g. aluminium salts; and ammonium salts.
  • Salts with suitable organic bases for example, salts with hydroxylamine; lower alkylamines, e.g. methylamine or ethylamine; with substituted lower alkylamines, e.g. hydroxy substituted alkylamines; or with monocyclic nitrogen heterocyclic compounds, e.g. piperidine or morpholine; and salts with amino acids, e.g.
  • the salts are non-toxic physiologically acceptable salts, although other salts are also useful, e.g. in isolating or purifying the product.
  • Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation.
  • the various optical isomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques.
  • the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation.
  • alkyl may represent include methyl, ethyl, butyl, and sec butyl.
  • aryl may represent include C 5 -Ci 0 carbocycles, which may be mono- or bicyclic, and partially or fully aromatic, optionally substituted by one or more halogens.
  • Halogen may represent F, Cl, Br and I.
  • the compounds have formula Ia, wherein: three of A 1 , A 2 , A 3 , and A 4 represent CH and one of A 1 , A 2 , A 3 , and A 4 represents CR 1 wherein R 1 represents SO 2 R 2 or NHCOR 2 wherein R 2 represents Ci-C 6 alkyl optionally substituted by one or more halogen, hydroxyl or Ci -6 alkoxy groups; and R 9 represents C 6 -Ci 0 aryl.
  • R 9 represents 2- naphthyl or 4-chlorophenyl.
  • a 1 , A 2 and A 4 represent CH and A 3 represents CR 1 .
  • R 2 is ethyl or isopropyl.
  • the compounds of formula I for use in the treatment of DMD will generally be administered in the form of a pharmaceutical composition.
  • a pharmaceutical composition including in one embodiment less than 80% w/w, in another embodiment less than 50% w/w, e.g. 0.1 to 20%, of a compound of formula I, or a pharmaceutically acceptable salt thereof, as defined above, in admixture with a pharmaceutically acceptable diluent or carrier.
  • a process for the production of such a pharmaceutical composition which comprises mixing the ingredients.
  • suitable diluents or carriers are as follows: for intravenous injection or infusion - purified water or saline solution; for inhalation compositions - coarse lactose; for tablets, capsules and dragees - microcrystalline cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, sodium bicarbonate and/or geiaiin; for suppositories - natural or hardened oils or waxes.
  • chelating or sequestering agents antioxidants, tonicity adjusting agents, pH-modifying agents and buffering agents.
  • Solutions containing a compound of formula I may, if desired, be evaporated, e.g. by freeze drying or spray drying, to give a solid composition, which may be reconstituted prior to use.
  • the compound of formula I in one embodiment, is in a form having a mass median diameter of from 0.01 to lO ⁇ m.
  • the compositions may also contain suitable preserving, stabilising and wetting agents, solubilisers, e.g. a water-soluble cellulose polymer such as hydroxypropyl methylcellulose, or a water-soluble glycol such as propylene glycol, sweetening and colouring agents and flavourings. Where appropriate, the compositions may be formulated in sustained release form.
  • the content of compound formula I in a pharmaceutical composition is generally about 0.01-about 99.9wt%, in one embodiment about 0.1-about 50wt%, relative to the entire preparation.
  • the dose of the compound of formula I is determined in consideration of age, body weight, general health condition, diet, administration time, administration method, clearance rate, combination of drugs, the level of disease for which the patient is under treatment then, and other factors. While the dose varies depending on the target disease, condition, subject of administration, administration method and the like, for oral administration as a therapeutic agent for the treatment of Duchenne muscular dystrophy in a patient suffering from such a disease is from 0.01 mg - 10 g, in one embodiment 0.1 - 100 mg, is in one embodiment administered in a single dose or in 2 or 3 portions per day.
  • the potential activity of the compounds of formula I for use in the treatment of DMD may be demonstrated in the following predictive assay and screens.
  • the cell line used for the screen is an immortalized mdx mouse H2K cell line that has been stably transfected with a plasmid containing ⁇ 5kb fragment of the Utrophin A promoter including the first untranslated exon linked to a luciferase reporter gene (see Figure 1).
  • the cells Under conditions of low temperature and interferon containing media, the cells remain as myoblasts. These are plated into 96 well plates and cultured in the presence of compound for three days. The level of luciferase is then determined by cell lysis and reading of the light output from the expressed luciferase gene utilising a plate luminometer.
  • ADMET data Data obtained from the ADMET data was prioritised and the compounds with the best in vitro luciferase activity and reasonable ADMET data were prioritised for testing in the mdx proof of concept study where the outcome was to identify whether any of the compounds had the ability to increase the levels of utrophin protein in dystrophin deficient muscle when compared to vehicle only dosed control animals.
  • Figure 3 shows an example of TA muscle sections stained with antibody specific for mouse utrophin. Comparison to the mdx muscle only injected with vehicle shows an increase in the amount of sarcolemmal bound utrophin.
  • Muscles from the above treated mice were also excised and processed for Western blotting and stained with specific antibodies (see Figure 4). Again using muscle dosed with CPD-A shows a significant increase in the overall levels of utrophin present in both the TA leg muscle and the diaphragm. Both mice exposed to CPD-A (V2 and V3) showed increased ! -Tv els of utrophin expression compared to control.
  • the H2K/mdx/Utro A reporter cell line maintenance The H2K/mdx/Utro A reporter cell line was passaged twice a week until ⁇ 30% confluent .
  • the cells were grown at 33 0 C in the presence of 10% CO 2 .
  • the H2K/mdx/Utro A reporter cell line cells were plated out into 96 well plates (Falcon 353296, white opaque) at a density of approximately 5000 cells/well in 190 ⁇ l normal growth medium. The plates were then incubated at 33 0 C in the presence of 10% CO 2 for 24 hrs. Compounds were dosed by adding 1 O ⁇ l of diluted compound to each well giving a final concentration of lO ⁇ M. The plates were then incubated for a further 48hrs.
  • Mdx from a breeding colony were selected for testing. Mice were injected daily with either vehicle or 10mg/kg of compound using the intreperitoneal route (ip). Mice were weighed and compounds diluted in 5% DMSO, 0.1% tween in PBS.
  • mice were sacrificed by cervical dislocation at desired time points, and muscles excised for analysis.
  • Biological activity was assessed using the luciferase reporter assay in murine H2K cells, and is classified as f ⁇ llows: + Up to 200% relative to control
  • HPLC-UV-MS was performed on a Gilson 321 HPLC with detection performed by a Gilson 170 DAD and a Finnigan AQA mass spectrometer operating in electrospray ionisation mode.
  • the HPLC column used is a Phenomenex Gemini Cl 8 150x4.6mm.
  • Preparative HPLC was performed on a Gilson 321 with detection performed by a Gilson 170 DAD. Fractions were collected using a Gilson 215 fraction collector.
  • the preparative HPLC column used is a Phenomenex Gemini Cl 8 150x 10mm and the mobile phase is acetonitrile/water. 1 H NMR spectra were recorded on a Bruker instrument operating at 300 MHz.
  • NMR spectra were obtained as CDCl 3 solutions (reported in ppm), using chloroform as the reference standard (7.25 ppm) or DMSO-D 6 (2.50 ppm).
  • peak multiplicities the following abbreviations are used s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets).
  • Coupling constants when given, are reported in Hertz (Hz).
  • reaction is allowed to cool down to room temperature.
  • crude reaction mixture was dissolved in EtOAc and filtered through celite.
  • the celite was washed three times with EtOAc, concentrated in vacuo.
  • Iron powder (116mg, 5eq, 2.07mmol) was then added to the mixture.
  • the reaction was heated for 12 hours at 8O 0 CNo starting material was left y TLC.
  • the reaction mixture was allowed to cool down to room temperature and filtered through celite.
  • the celite was washed three times with THF, concentrated in vacuo.
  • the residue was dissolved in EtOAc, washed twice with H 2 O and once with brine.
  • the organic phases were combined, dried over sodium sulfate and concentrated in vacuo. No purification attempted
  • the crude aniline C or D (130mg, leq, 0.5mmol) was dissolved in pyridine (8mL) and the isobutyrylchloride was added drop wise at room temperature. The reaction mixture was left stirring at room temperature for 18 hours. No starting material was observed by TLC after 18 hours. The reaction mixture was diluted with CuSO 4 a q > extracted three times with EtOAc . The combined organic phases were washed once with brine and H 2 O, dried over sodium sulfate and concentrated in vacuo.
  • Aqueous saturated ammonium chloride (1OmL) was added to the solution, the organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous MgSO 4 and evaporated.

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Abstract

L'invention concerne des composés de la formule (I) dans laquelle trois éléments parmi A1, A2, A3, et A4 représentent CH et un élément parmi A1, A2, A3, et A4 représente CR1; R1 représente SO2R2 ou NHCOR2 où R2 représente un C1-C6 alkyle facultativement substitué par un ou plusieurs groupes halogène, hydroxyle ou alcoxy; R9 représente un C6-C10 aryle; ou un sel pharmaceutiquement acceptable de ces derniers.
PCT/EP2008/006717 2007-08-15 2008-08-14 Traitement de la dystrophie musculaire de duchenne Ceased WO2009021747A2 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
AU2008286323A AU2008286323A1 (en) 2007-08-15 2008-08-14 Treatment of Duchenne muscular dystrophy
EP08785564A EP2176230A2 (fr) 2007-08-15 2008-08-14 Traitement de la dystrophie musculaire de duchenne
JP2010520497A JP2010535828A (ja) 2007-08-15 2008-08-14 デュシェンヌ型筋ジストロフィーの治療
CA002685582A CA2685582A1 (fr) 2007-08-15 2008-08-14 Traitement de la dystrophie musculaire de duchenne
US12/599,967 US20120149741A1 (en) 2007-08-15 2008-08-14 Treatment of duchenne muscular dystrophy

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0715938.7 2007-08-15
GBGB0715938.7A GB0715938D0 (en) 2007-08-15 2007-08-15 Method of treatment of duchenne muscular dystrophy

Publications (2)

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WO2009021747A2 true WO2009021747A2 (fr) 2009-02-19
WO2009021747A3 WO2009021747A3 (fr) 2009-04-02

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PCT/EP2008/006717 Ceased WO2009021747A2 (fr) 2007-08-15 2008-08-14 Traitement de la dystrophie musculaire de duchenne

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US (1) US20120149741A1 (fr)
EP (1) EP2176230A2 (fr)
JP (1) JP2010535828A (fr)
AU (1) AU2008286323A1 (fr)
CA (1) CA2685582A1 (fr)
GB (1) GB0715938D0 (fr)
WO (1) WO2009021747A2 (fr)

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US9138459B2 (en) 2004-07-23 2015-09-22 Acceleron Pharma Inc. ACTRIIB-FC polynucleotides, polypeptides, and compositions
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AU2007213451B2 (en) * 2006-02-10 2013-02-07 Summit (Oxford) Limited Treatment of Duchenne muscular dystrophy
WO2007091107A1 (fr) * 2006-02-10 2007-08-16 Summit Corporation Plc Traitement de la dystrophie musculaire de duchenne
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US9572865B2 (en) 2005-11-23 2017-02-21 Acceleron Pharma Inc. Activin-actriia antagonists and uses for treating multiple myeloma
US9163075B2 (en) 2005-11-23 2015-10-20 Acceleron Pharma Inc. Isolated polynucleotide that encodes an ActRIIa-Fc fusion polypeptide
US10239940B2 (en) 2005-11-23 2019-03-26 Acceleron Pharma Inc. Method of promoting bone growth by an anti-actriia antibody
US9480742B2 (en) 2005-11-23 2016-11-01 Acceleron Pharma Inc. Method of promoting bone growth by an anti-actriia antibody
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US11129873B2 (en) 2005-11-23 2021-09-28 Acceleron Pharma Inc. Method for promoting bone growth using activin-actriia antagonists
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WO2009021747A3 (fr) 2009-04-02
JP2010535828A (ja) 2010-11-25
GB0715938D0 (en) 2007-09-26
US20120149741A1 (en) 2012-06-14
AU2008286323A1 (en) 2009-02-19
CA2685582A1 (fr) 2009-02-19

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